Stopping the Obesity Cycle

Obesity is associated with an increase in lipid storage in adipocytes and a consequent increase in adipocyte size. Changes in cell size affect the cytoskeleton, which is regulated by molecules such as the guanosine triphosphatase Rho and its effector Rho-kinase. Noting that mechanical stretch can lead to activation of the Rho to Rho-kinase (Rho–Rho-kinase) signaling pathway, Hara et al. investigated the role of Rho–Rho-kinase signaling in obesity and its complications. They found that adipocyte Rho-kinase signaling was increased in obese mice fed a high-fat diet. Rho-kinase activity in adipocytes increased with increasing cell size and was also activated by mechanical stretch. Inhibition of Rho-kinase signaling—either systemically or specifically in adipocytes—inhibited the development of an inflammatory obesity-related phenotype in adipose tissue. Moreover, it decreased weight gain in mice fed a high-fat diet and attenuated such pathophysiological complications of obesity as insulin resistance and glucose intolerance. The authors thus propose that adipocyte stretch may contribute to obesity and its complications through activation of Rho–Rho-kinase signaling and that inhibition of this signaling pathway may provide a mechanism for disrupting this cycle.